There are only three vaccines that are licensed globally for immunization at birth: Bacille Calmette-Guérin (BCG) to prevent tuberculosis, oral Polio vaccine (OPV), and hepatitis B vaccine (HBV). Sanchez-Schmitz et al., Sci. Transl. Med. 3, 90ps27 (2011). BCG is a single-dose vaccine of freeze-dried, live Mycobacterium bovis. Id. OPV is a single-dose vaccine of a live-attenuated poliovirus. Id. HBV vaccine is a recombinant hepatitis B surface antigen expressed in yeast that is administered with Alum in three-doses, starting at birth. Id. Thus, two of these are live, replicating vaccines, and the other is a recombinant protein given in three doses.
The immaturity of the immune system in newborns has been a major bottleneck to develop safe and effective vaccines at this age. Under the current vaccination schedule for infants, only the Hepatitis B vaccine is recommended at birth, while others are given later during infancy (first 12 months, e.g. rotavirus, inactivated poliovirus vaccine), or are only recommended at 12 months or older (e.g. measles/mumps/rubella vaccine), although in all cases multiple vaccinations are required during infancy/childhood to induce high levels of protection. Sanchez-Schmitz et al., Sci., there is a time span of six to nine months after birth with increased susceptibility to diseases that could be prevented by vaccines. Id. Smallpox, AIDS, malaria, tuberculosis, and other diseases occur in young children with a rapid and often severe disease progression. Even for childhood diseases such as RSV or measles, vaccines do not exist or cannot be administered before 9 months of age. Consequently, vaccination of neonates (within first 4 weeks) and/or a reduced or more effective schedule in infants would be a major advance in reducing mortality and morbidity associated with infectious diseases.
It is generally accepted that newborns mount mainly TH2 biased T-cell responses and produce no or only low levels of antibodies with limited affinity. In addition, these responses are of shorter duration than in adults. Adkins et al., Nat. Rev. Immunol. 4, 553-564 (2004); Marshall-Clarke et al., Immunol. Today 21, 35-41 (2000); Siegrist, C. A., Vaccine 19, 3331-3346 (2001).
However, under certain circumstances, such as activation of pattern recognition receptors or during certain viral infections, newborn mice can mount protective T-cell responses over time, indicating the potential for neonatal immunization. Forsthuber et al., Science 271, 1728-1730 (1996); Sarzotti et al., Science 271, 1726-1728 (1996).
Parallel to the development of adjuvants improving existing vaccines (Gracia et al., Vaccine 29, 1595-1604 (2011); Kamath et al., PLoS. One. 3, e3683 (2008)), new antigen delivery systems like DNA vaccines (Hassett et al., J. Virol. 74, 2620-2627 (2000); Rigato et al., Virology 406, 37-47 (2010)) and the three attenuated replicating bacterial strains Salmonella enteric (Ramirez et al., Vaccine 28, 6065-6075 (2010)), Listeria monocytogenes (Kollmann et al., J. Immunol. 178, 3695-3701 (2007)), and BCG (Nascimento et al., Microbes. Infect. 10, 198-202 (2008); Ranganathan et al., Vaccine 28, 152-161 (2009)) were shown to induce efficient immune responses when administered in one week old mice or even at birth. However, only live attenuated replicating vaccines induced protection against lethal infections, and were generally effective only after several immunizations and thus at a stage with a progressed immunological maturity. Hence, replicative vaccines require substantial time to induce successful protection, and the risk of uncontrolled disseminated infections of live attenuated replicating vaccines still represent major limitations (Galen et al., Immunol. Cell Biol. 87, 400-412 (2009); Johnson et al., Microbiol. Immunol. 55, 304-317 (2011); Li et al., Zhonghua Er. Ke. Za Zhi. 48, 65-68 (2010); Liu et al., Immunol. Rev. 239, 62-84 (2011)).
Modified Vaccinia virus Ankara (MVA) has been administered to over 100,000 individuals during the smallpox eradication campaign without any complications. However, MVA still represents a complex mixture of viruses with different levels of attenuation and immunogenicity. Suter et al., Vaccine 27, 7442-7450 (2009). The plaque-purified MVA developed by Bavarian Nordic (MVA-BN) completely fails to replicate in mammals including humans and is safe even in immune-compromised hosts. Id. Besides its excellent safety profile, MVA is highly immunogenic in humans (Vollmar et al., Vaccine 24, 2065-2070 (2006)) and its efficacy has been proven in several smallpox animal models such as Ectromelia virus (ECTV), rabbitpox or monkeypox (Garza et al., Vaccine 27, 5496-5504 (2009); Samuelsson et al., J. Clin. Invest 118, 1776-1784 (2008); Stittelaar at al., J. Virol. 79, 7845-7851 (2005)). Another major advantage of MVA is its capacity to support the genetic insertion of several antigens (Timm et al., Vaccine 24, 4618-4621 (2006)) that could concomitantly induce protection against other infectious diseases or cancer ((Harrer et al. Antivir. Ther. 10, 285-300 (2005); Mandl et al., Cancer Immunol. Immunother. (2011); Meyer et al., Cancer Immunol. Immunother. 54, 453-467 (2005)).
ECTV (the causative agent of mousepox) in mice is a good model system for human poxvirus infection. Esteban et al., Journal of General Virology (2005), 86, 2645-2659. The course of disease is very similar for mousepox and smallpox, including the entry route, the high infectivity at low doses, the development of viremia, the restricted host range, and the delayed but fatal outcome. Therefore, mousepox can be regarded as a valuable small animal model for human smallpox and, in general, as a model for acute, fatal viral diseases. Lauterbach et al., PLoS ONE, Volume 5(3): e9659 (2010).
The pathogenesis of ECTV infection in mice, with localized replication and systemic spread, is similar to the pathogenesis of Variola virus in humans. Chapman et al., Vet Pathol 2010 47: 852 (2010). A comparison of short-term and postexposure protection in mice infected with VACV-WR and ECTV suggested that ECTV infection more closely resembles human smallpox. Paran et al., The Journal of Infectious Diseases; 199:39-48 (2009).
The vaccination of mice with MVA at birth is safe and induces an increase of FLT3 ligand, leading to an accelerated development of plasmacytoid dendritic cells (pDC) and activation of conventional (c) DC resulting in improved resistance against heterologous viral infection. (Franchini at al., J. Immunol. 172, 6304-6312 (2004), Vollstedt et al., Eur J Immunol. 34: 1849-1860 (2004) Vollstedt et al., Eur J Immunol. 36: 1231-1240 (2006). Vaccination of one or two-day old mice with 2.5×107 TCID50 of MVA protected most mice against challenge with a lethal dose of herpes simplex virus 1 (HSV-1) at 7-8 days after vaccination and protected most mice against challenge with a lethal dose of vaccinia Western Reserve (VV-WR) at 4 weeks after immunization, when the mice were considered adults. WO 03/088994A2. To determine the virus dose needed for maximal induction of CD11c+ cells, graded doses of MVA were tested. Maximal numbers of CD11c+ cells were detected after treatment with 2.5×106 TCID50 of virus; whereas, doses below and above this were less effective. Id. Thus, 2.5×106 TCID50 was considered to be the optimal dose of MVA for the vaccination of neonates.
Consequently, a need in the art exists for compositions and methods for vaccination of neonates to achieve strong T-cell and antibody responses and protection against pathogens. The invention fulfills this need.